Bacterial infections are often accompanied by inflammation of the infected tissues. For example, during the pathogenesis of periodontal disease, it is generally accepted that while bacteria cause tissue destruction via release of virulence factors, a major role has been proposed for the host itself. The current concept is that the bacteria produce inflammogens including lipopolysaccharides, which trigger mononuclear host cells resulting in bone and connective tissue destruction. These destructive mechanisms include periodontal triggering of macrophage and collagenase which degrades tissue collagen, and stimulation of the production, by mononuclear cells, of interleukin-2 and other cytokines which stimulates local bone resorption.
While antibiotics have been used to treat periodontitis, recent studies show that anti-inflammatory agents also reduce chronic destructive periodontitis (Williams et al., 1989, J. Periodontology, 60:485-490; Reddy et al., 1993, J. Clinical Periodontology 20:635-640). Most of the anti-inflammatory approaches used so far utilize the systemic non-steroidal anti-inflammatory flurboprofen which has a risk of adverse systemic effects such as gastric ulcers. Furthermore, most anti-inflammatory agents that have been proposed for topical application are designed for systemic use and hence have significant systemic absorption potential, especially when used over long periods of time.
In another inflammatory condition, acne, it is generally accepted that there is increased sebum production in and around sebum producing glands in the skin (Abel et al., 1990, Scientific Americal Medicine, 1:212-2110). One of the most frequently occurring severe forms of acne, acne vulgaris, is a chronic disorder of pilosebaceous units primarily on the chest, Ad face, and back, resulting in the formation of large, pus filled lesions accompanied by inflammation of the surrounding tissue.
Many products with different mechanisms of action are currently marketed to treat acne. Quite often the -choice of a particular product depends on the severity of the acne being treated and the side effects that can be associated with the chosen treatment. Some treat acne through the use of antibiotics that kill bacteria and indirectly reduce inflammation. These antibiotics are lipophilic, tending to concentrate in lipid rich sedum and include tetracycline, meclocycline, erythromycin, clindamycin, nadifloxacine. A second family of products use the retinoid class of drugs which function by reducing sebum production. The final class of products are over-the-counter drugs of the keratolytic class which loosen plugs in comedones created by excess sebum and thus rid the skin of dead cells and cell debris. Active ingredients in over-the-counter treatments which perform these functions include benzoyl peroxide, resorcinol, salicylic acid, and sulfur.
Although prescription antibiotics are used for treating severe acne, there are two major problems with their use. First, there has been an increase in bacterial resistance to antibiotics. Second, there is the concern that a prescribed antibiotic can have serious side effects. Currently sold "over-the-counter" formulations that list antibacterial claims are generally effective only at treating mild cases of acne.
Other approaches to treat inflammatory condition include the use of salicylanilides (U.S. Pat. No. 4,742,083) of the general formula: ##STR2## wherein R.sub.1, R.sub.2 and R.sub.3 are defined hydrocarbon attachments and Y is --OH or a phenolic ester group. These salicylanilide derivatives have also been shown to be effective anti-plaque agents (U.S. Pat. No. 4,287,191 and U.S. Pat. No. 2,358,443). The most effective of these compounds is defined by the formula: ##STR3## where n=6, X is ##STR4## and --R.sub.3 is a meta-trifluoromethylphenyl group (AMCF3-8). This compound has a pKa of 6.1 rendering it relatively insoluble in aqueous solutions at neutral pH.
U.S. Pat. No. 5,2406,696 discloses the use of 2',4,4'-trichloro-2-hydroxy-diphenyl-ether (Triclosan.TM.) as an anti-inflammatory agent against periodontitis.
Thus, currently available topical antiinflammatory compounds have either high systemic absorption or low solubility in formulations typically used in topical applications. A need therefore exists for effective anti-inflammatory compounds, which are also useful in chronic inflammatory condition, that are lipophilic thereby reducing the risk of systemic absorption, and are also easily solubilized in formulations suitable for topical application.